Dataset Information

Upadacitinib in Rheumatoid Arthritis: A Benefit-Risk Assessment Across a Phase III Program.

ABSTRACT: Treating to a target of clinical remission or low disease activity is an important principle for managing rheumatoid arthritis (RA). Despite the availability of biologic disease-modifying antirheumatic drugs (bDMARDs), a substantial proportion of patients with RA do not achieve these treatment targets. Upadacitinib is a once-daily, oral Janus kinase (JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2. The SELECT phase III upadacitinib clinical program comprised five pivotal trials of approximately 4400 patients with RA, including inadequate responders (IR) to conventional synthetic (cs)DMARDs or bDMARDs. This review aims to provide insights into the benefit-risk profile of upadacitinib in patients with RA. Upadacitinib 15 mg once daily, in combination with csDMARDs or as monotherapy, achieved all primary and ranked secondary endpoints in the five pivotal trials across csDMARD-naïve, csDMARD-IR, and bDMARD-IR populations. Upadacitinib 15 mg also demonstrated significantly higher rates of remission and low disease activity in all five pivotal trials, compared with placebo, methotrexate, or adalimumab. Labeled warnings of JAK inhibitors include serious infections, herpes zoster, malignancies, major cardiovascular events, and venous thromboembolic events. Short- and long-term integrated analyses showed that upadacitinib 15 mg was associated with increased risk of herpes zoster and creatine phosphokinase elevations compared with methotrexate and adalimumab but otherwise had comparable safety with these active comparators. This review suggests that upadacitinib 15 mg had a favorable benefit-risk profile. The safety of upadacitinib will continue to be monitored in long-term extensions and post-marketing studies.

SUBMITTER: Conaghan PG

PROVIDER: S-EPMC8053169 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionTo compare the economic benefit of upadacitinib combination therapy versus tofacitinib combination therapy and upadacitinib monotherapy versus methotrexate monotherapy from improvements in health-related quality of life (HRQOL) in patients with rheumatoid arthritis (RA).MethodsData were analyzed from two trials of upadacitinib (SELECT-NEXT and SELECT-MONOTHERAPY) and one trial of tofacitinib (ORAL-Standard) that collected HRQOL measurements using the Short Form 36 (SF-36) Health Survey in patients with RA. Direct medical costs per patient per month (PPPM) for patients receiving upadacitinib 15 mg once daily and methotrexate were derived from observed SF-36 Physical (PCS) and Mental Component Summary (MCS) scores in the SELECT trials using a regression algorithm. Direct medical costs PPPM for patients receiving tofacitinib 5 mg twice daily were obtained from a published analysis of SF-36 PCS and MCS scores observed in the ORAL-Standard trial. Short-term (12-14 weeks) and long-term (48 weeks) estimates of direct medical costs PPPM were compared between upadacitinib and tofacitinib and between upadacitinib and methotrexate.ResultsOver 12 weeks, direct medical costs PPPM were $252 lower (95% CI $72, $446) for upadacitinib-treated patients versus tofacitinib-treated patients. Medical costs PPPM at weeks 24 and 48 and cumulative costs over the entire 48-week period (difference $1759; 95% CI $1162, $2449) were significantly lower for upadacitinib than for tofacitinib. Over 14 weeks, direct medical costs PPPM were $399 lower (95% CI $158, $620) for patients treated with upadacitinib monotherapy compared with those treated with methotrexate alone. Direct medical costs at week 48 and cumulative costs over the entire 48-week period (difference $2044; 95% CI $1221, $2846) were significantly lower for upadacitinib monotherapy compared with methotrexate alone.ConclusionIn the short and long term, upadacitinib combination therapy versus tofacitinib combination therapy and upadacitinib monotherapy versus methotrexate monotherapy were associated with significantly lower direct medical costs for patients with RA.Trial registrationClinicalTrials.gov identifier, NCT02675426, NCT02706951, and NCT00853385.

Project description:Background and objectivesUpadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I-III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations.MethodsPharmacokinetic data from 4170 subjects taking IR doses of 1-48 mg and ER doses of 7.5-30 mg across 12 studies spanning phase I-III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks.ResultsA two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration-time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration-time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were?<?60 or?>?100 kg, respectively, relative to subjects with a bodyweight of 60-100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure.ConclusionsA robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I-III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure-response relationship of upadacitinib.

Project description:BACKGROUND AND OBJECTIVES:Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS:Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations. RESULTS:A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight. CONCLUSIONS:Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure. TRIAL REGISTRATION:ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.

Dataset Information

Upadacitinib in Rheumatoid Arthritis: A Benefit-Risk Assessment Across a Phase III Program.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets